Anthelmintic 5-(pyridyl)-3-(isothiocyanophenyl) oxadiazoles

ABSTRACT

5-(Heterocyclyl)-3-(isothiocyanophenyl)oxadiazoles and related compounds and their methods of preparation are disclosed. In addition, useful compositions and methods for employing said compositions as anthelmintics are taught.

Maire States Patent [1 1 Narayanan et al.

[ ANTHELMINTIC 5-(PYRIDYL)-3-(ISOTHIOCYANOPHENYL) OXADIAZOLES [75] Inventors: Venkatachala Lakshmi Narayanan,

Hightstown; Rudiger Dieter Haugwitz, Titusville, both of NJ.

[73] Assignee: E. R. Squibb & Sons, Inc.,

Princeton, NJv

[22] Filed: Apr. 2, 1973 [21] Appl. No.: 347,312

[451 Dec. 10, 1974 [56] References Cited UNITED STATES PATENTS 3,647,809 3/1972 Harsanyi et a]. 260/296 R 3,651,054 3/1972 Crovetti et al'. 260/296 R Primary Exa minerAlan L. Rotman Attorney, Agent, or FirmLawrence S. Levinson; Merle J. Smith; Stephen B. Davis [5 7] ABSTRACT 5-(Heter0cyclyl)-3-(isothiocyanophenyl)oxadiazoles and related compounds and their methods of preparation are disclosed. In addition, useful compositions and methods for employing said compositions as anthelmintics are taught.

7 Claims, N0 Drawings N O l L S mg)! The term aryl is intended to include phenyl, naph-' thyl, substituted phenyl wherein said substituent may be fluoro, chloro, bromo, iodo, nitro, trifluoromethyl, lower alkyl and lower alkoxy.

The term lower alkyl is intended to mean a straight or branched, hydrocarbon fragment of from one to eight carbon atoms, such as methyl, propyl, t-butyl, etc.

The term lower alkoxy is intended to mean a lower alkyl group linked through a single bond to oxygen.

The term halogen is intended to mean chloro, bromo" or fluoro.

The term heterocyclic ring is intended to mean a five or six membered heterocyclic ring containing from one to three heteroatoms, selected from the group consisting of oxygen, nitrogen and sulfur. Examples of such heterocyclic rings are thiophene, furan, thiazole, pyridine, pyrrole, pyrazine, imidazole, oxazole, morpholine, etc.

In addition, the term heterocyclic ring from one to three heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur is intended to also encompass said heterocycles in their reduced form containing two, four, or six additional hydrogen atoms, such as N-methylpiperizine and said heterocycles which are substituted by a lower alkyl groupor lower alkoxy group.

" The term pharmaceutically acceptable salts is intended to mean the relatively nontoxic acid addition salts, such as the hydrochloride, sulfate, phosphate, acetate, maleate, citrate, etc.

The compounds of this invention are prepared in the following manner:

NH IL -CN -NHO1[ om l on: I

The nitrobenzonitriles of formula II are converted to amidoximes of the formula III by treatment with an acid salt of hydroxylamine, such as the hydrochloride, sulfate or phosphate in the presence of an acid acceptor, such as sodium or potassium carbonate. The reaction is generally conducted in an aqueous or nonaqueous alcohol solvent of up to four carbon atoms at from about room temperature to the reflux temperature of the solvent for periods of from 1 to 48 hours,

preferably about 2 4 hours.

'N l l HI 1 N X/ N-() R W R v Oxadiazoles of the formula IV, wherein R is a heterocyclic ring are prepared by heating a compound of the formula:

I I ll R halide or R1 0 CR1 with a compound of formula III.

In many instances, the acylating agent may be used in excess thus also serving as the solvent medium; however, generally in inert organic solvent, such as benzene or ether is employed. The temperature range generally employed is either the refluxing temperature of the solvent or about C whichever is the lesser, and the time ranges from about a few minutes to about 8 hours. This reaction is preferably conducted in the presence of a catalytic amount of BF -etherate.

Compounds of the type IV are converted to those of the formula V in poor yield, utilizing reducing agents such as PtO /H Na S O /CH OH, Pd/H N H Pd/C, and NaBl-I S /TI-IF. Surprisingly, catalytic reduction using about 5% Pd/C in the presence of about 2-5 equivalents of an acid, such as hydrochloric acid or sulfuric acid, gives good yields of amino compounds.

The conversion of the amines of formula V into the (isothiocyanophenyl) oxazoles (I) of this invention may be achieved by reacting the amine with:

i ClCCl in a relatively non-polar solvent, such as chloroform, ether, tetrahydrofuran, etc., preferably in the presence of an acid acceptor, such as calcium carbonate, trimethylamine, etc. at temperatures from 0 to 60C. More specific reaction procedures are disclosed in HoubenWeyl, 4th Edition, Vol. 9, pages 867 and 88 (1955) and the use of acid binding agents is disclosed in Arch. Pharm. 295, 146-151 (1962).

b. N,N-di(lower alkyl)thiocarbamoyl halide, wherein said halo atom is chlorine or bromine, in an organic solvent, such as benzene, toluene, ethylene'dichloride or chlorobenzene at temperatures of from about 40 to about 200C [J Org Chem 30, 2465 (1965)] c. a bis-thiocarbamoyl sulfide of the formula 8 lower alk yl lower alkyl lower alkyl S lower alkyl wherein m is one or two and lower alkyl in preferably ethyl in the presence of an hydrogen halide at room temperature to the refluxing temperature of the organic solvent used, such as chlorobenzene [Helv. Chim. Acta 49, 1716 (1966)].

f. phosgene and phosphorus pentasulfide in the gen eral manner described in I-louben-Weyl, 4th Edition, Vol. 9, pages 867 and 88 (1955).

g. carbon disulfide in the presence of an inorganic or organic base, such as triethylamine, potassium carbonate, etc. followed by oxidative dehydrosulphurisation with a metal salt (British Patent No. 793,802) such as lead, copper, zinc or iron (III) salts, iodine, alkalimetal hypochlorites or chlorites,

' preferably the sodium or potassium salts (French Patent Ono. 1,31 1,855), acid halides such as phosgene and phosphorus oxychloride [Chem Ber. 98, 2425-2426 (1965], chlorine and ammonium sulfide (DAS 1,198,189) or chloramine T (British Patent No. 1,024,913).

h. ammonium rhodanide and benzoyl chloride, followed by thermal decomposition in a refluxing solvent such as chlorobenzene [I-Iouben-Weyl, 4th Edition, 9, 867 and 88 (1955)].

i. carbon disulfide, dicyclohexyl carbodiimide and a tertiary amine such as pyridine or triethylamine at temperatures of from about 10 to about 30C for from about 0.5 to about 24 hours [Chem Ber. 101, 1746 (1968}.

The publications cited for the introduction of the isothionato group are incorporated by reference.

The preferred compounds and starting materials prepared by the above procedures are those wherein R is hydrogen or chlorine and R is thienyl, thiazolyl, pyridyl, furyl or pyrryl.

The compounds described herein have anthelmintic activity and are useful in the treatment and/or prevention of helminthiasis, a parasitic disease which causes widespread and often serious infection in domesticated animals such as swine, horses, cattle, dogs, cats and sheep. While the compounds are preferably used in the treatment of hookworm (Ancylostoma canium and Uncinaria stenocephala) and roundworm (Toxccara canis and Toxescaris Ieonina), other compounds are also highly useful in treating infections caused by haemonchus, ostertagia, trichostrongylus, cooperia, nematodirus, bunostomum, strongylorides, oesophagostomum,

trichiuris and moniezia. In treating domesticated'animals, the compounds are given orally and may be mixed with a nontoxic, edible carrier to form a feed supplement, or be administered in unit dosage'forms such as powders, capsule, tablet, boluses, drenches,

etc.

In general, the compounds of this invention (1) exhibit anthelmintic activity when administered to animals in a daily dose of about 10 to about 200 mg per kilogram of animal body weight. It is preferred to employ in the range of 20-100 mg per kilogram of body weight per day. The compounds may be given in a single dose or divided into a plurality of smaller doses. When the compounds are to be employed primarily as prophylactic agents for the prevention of helminthic infections, the preferred daily dose level is, of course, lower than the therapeutic level is, preferably in the range of about 2-20 mg per kilogram of body weight.

When the compounds of this invention are to be administered in unit dosage form, capsules, boluses or drenches containing the desired amount of anthelmintic distributed in a pharmaceutically acceptable vehicle are usually employed. These are prepared by intimately and uniformly mixing the active ingredient with suitable finely divided diluents, suspending agents, fillers, disintegrating agents and/or binders such as starch, lactose, talc, magnesium stearate, vegetable gums and the like and are compounded by techniques generally known in the art.

The compounds of this invention may also be administered as a component of the feed of the animals or suspended in the drinking water. Thus, novel feed and feed supplement compositions may be prepared in which the compounds of this invention are present as 'an active anthelmintic ingredient. A typical feed supplement comprises the anthelmintic agent (5-50%, preferably 1030%) intimately dispersed in or admixed with an inert carrier or diluent, i.e., one that is nonreactive with respect to the anthelmintic agent and that may be administered with safety to the animals. The carrier or diluent is preferably one that is or may be an ingredient of an animal ration. This composition may be mixed with the feed to give any useful desired concentration, preferably about 0.l-2%. Lastly, feeds containing the active ingredient may be made directly by mixing said active ingredient in a feed which is inert to said anthelmintic compounds so as to give feeds having concentrations of anthelmintic agent of from 0.12%.

DETAILED DESCRIPTION The following examples are provided for illustrative purposes and may include particular features of the invention; however, the examples should not be construed as limiting the invention, many variations of which are possible without departing from the spirit or scope thereof.

EXAMPLE 1 p-Nitrobenzamidoxime A solution of 29.6 g (0.20 mole) of pnitrobenzonitrile, 13.9 g (0.20 mole) of hydroxylamine, HCI, 13.8 g. (0.10 mole) of K CO in 700 ml of ethanol and ml of B 0 is refluxed for 20 hours, cooled and diluted with 200 ml of H 0. After removal of the ethanol by distillation in vacuo, the product precipitates out of the aqeuous residue. This product is collected by filtration, washed with H 0 and dried to yield 21.6 g (60%).

EXAMPLES 28 Substituted-nitrobenzamidoximes EXAMPLE 9 5-(Z-Thienyl)-3-(p-nitrophenyl)-1,2,4-oxadiazole To a solution of 9.1 g (0.05 mole) of pnitrophenylacetamidoxime in 300 ml of dioxane, is added 7.4 g (0.05 mole) of 2-thiophenecarboxylic acid chloride. After stirring at r.t. for 10 minutes, 2 m1 of BP -H O is added, and the mixture is then refluxed for 18 hours. The reaction mixture is then cooled followed by addition of H 0. The resulting precipitate is collected by filtration and washed with Et O to yield 8.4 g of product (61%).

EXAMPLE 10 5-(4-thiazole)-3-(p-nitrophenyl)-1,2,4-oxadiazole A solution of 2.0 g (0.02 mole) of 4- thiazolecarboxylic acid in 15 ml of thionyl chloride is refluxed for 2 hours. The thionyl chloride is then removed by distillation in vacuo, and the resulting solid residue is washed with a small amount of Pet. Et O. This acid chloride is then added to a solution of 2.9 g (0.02 mole) of p-nitrophenyl acetamidoxime and 1.0 ml of BF Et O in 100 ml of dioxane, and the resulting mixture is refluxed overnight. The reaction mixture is then cooled followed by the addition of H 0. The precipitated product is collected by filtration and washed with Et O to yield 3.1 g (70%).

EXAMPLES 1 1-17 S-(heterocyclyl)-3-(p-nitrophenyl)-1 ,2,4-oxadiazole According to the procedure of Example 9, upon sub- 6 5 2-thienyl )-3-( 3 -nitro-2-chlorophenyl)-1,2,4-

oxadiazole, 5 Z-thienyl )-3-( 4-nitro-3-trifl uorophenyl )-1 ,2,4-

oxadiazole, 5-(2-thienyl)3-(4-nitro-2-ethoxyphenyl)-1,2,4-

oxadiazole, 5-(2-thienyl)-3-(2-nitro-4-phenylphenyl)-1,2 ,4-

oxadiazole,

5-( 2-thienyl )-3-( 2-nitro-4-dimethylaminophenyl 1,2,4-oxadiazole, and 5-(2-thienyl)-3-(3-nitro-4-acetamidophenyl)-1,2,4-

oxadiazole respectively.

EXAMPLE l 8 lsothiocyanic acid, p-[5-(2-thienyl)-1,2,4-oxadiazo1-3-yl] phenyl ester, hydrate (1:1)

A suspension of 4.0 g (0.02 mole) of 5-( 2-thienyl)-3- (p-nitrophenyl)-1,2,4-oxadiazole in 200 ml of eth' anol containing 0.4 g of 5% Pd/C and 2 ml of conc. HCl was hydrogenated at 50 psi over a period of one hour. The catalyst was removed by filtration followed by removal of the ethanol by distillation in vacuo. The resulting residue was taken up in a mixture of ml of CHCl and 30 ml of H 0 containing 2.0 g (0.02 mole) of CaCO This mixture was cooled to 0 followed by the addition of 1.8 g (0.02 mole) of CSCl After stirring for 15 minutes at this temperature, the ice bath was removed and the mixture was allowed to stir for an additional 0.5 hour. The reaction mixture was then filtered and the organic layer was separated, washed with [-1 0 and dried over CaCl After removing the drying agent, the CHCl was removed by distillation in vacuo to yield a solid residue. This residue was washed with pet ether-Et o to yield 1.5 g of product (35%). Recrystallization from pet ether-Et o yielded an analytical sample, mp 148150.

EXAMPLE 19 lsothiocyanic acid, p-[5-(4-thiaz0lyl)-1,2,4-oxadiazol-3ryll-phenyl ester.

A suspension of 2.0 g (0.01 mole) of 5-(4-thiazole)- 3-(p-nitropheny1)-1,2,4-oxadiazole, 0.2 g of 5% Pd/C and 1.0 ml of conc. HCI in 200 ml of EtOH was hydrogenated at 50 psi over a period of one hour. The resulting amine was reacted with 1.2 g (0.01 mole) of CSCl and 1.2 g (0.01 mole) of CaCo in a mixture of 100 ml of CHCl and 30 ml of H 0. The product yield was 0.9 g (43%).

EXAMPLE 20 lsothiocyanic acid, p-[5-(2-furyl)-1 ,2,4-oxadiazol-3-yl]-pheny1 ester This synthesis was carried out as described in example 18. A suspension of 5.1 g (0.02 mole) of 3-(pnitrophenyl)-5'(2-furyl)-l,2,4-oxadiazole, 0.5 g of 5% Pd/C and 2 ml of cone. HCl in 200 m1 of EtOI-l is hydrogenated at 50 psi over a period of 1 hour. The resulting amine is reacted with 2.5 g (0.02 mole) of CSCl and 2.5 g (0.03 mole) of CaCO in a mixture of 100 m1 of CHCl and 30 m1 of 11 0. The reaction yields 3.1 g (57%) of product. Recrystallization from petroleum ether-Et O yields an analytical sample, mp 137-140.

EXAMPLES 21-27 lsothiocyanic acid, p-['5-(2-thieny1)- l ,2 ,4oxadiazol-3-yl -phenyl esters According to the procedure of example 18, upon substituting in place of -(2-thienyl)-3-(p nitrophenyU-l,2,4-oxadiazole, one of the following:

5 2-thienyl )-3-( 2-nitr0-3 -methylphenyl)-1 ,2,4-

oxadiazole, 5-(2-thienyl)-3-(3-nitro-2-chlorophenyl)-1,2,4-

oxadiazole,

S-(Z-thienyl)-3-(4-nitro-3-trifluorophenyl)-1 ,2,4-

oxadiazole,

S(2-thienyl)-3-(4-nitro-2-ethoxyphenyl)- 1,2,4oxadiazole,

5-(2-thienyl)-3-(2-nitro-4-phenylphenyl)-1,2,4-

'oxadiazole, 5-(2-thienyl)-3-(2-nitro-4-dimethylaminophenyl)- 1,2,4-oxadiazole, and

5 ('2-thienyl )-3-( 3-nitro-4-acetamidophenyl )-1 ,2,4-

oxadiazole, one obtains:

isothiocyanic acid, 2-(5-(2-thie'nyl)-l,2,4-oxadiazol- 3-yl 6-methylphenyl ester, isothiocyanic acid, 3-(5-(2-thienyl)-l,2,4-oxadiazol- 3-yl)-2-ch1orophenyl ester,

isothiocyanic acid, 4-(5-(2-thienyl)-1,2,4-oxadiazol- 3-yl)-2-trifluoromethylphenyl ester,

isothiocyanic acid, 4-(5-(2-thienyl)-1,2,4-oxadiazol- 3-yl )-3-ethoxyphenyl ester,

isothiocyanic acid, 2-(5-(2-thieny1)-l,2,4-oxadiazol- 3-yl)-5-(phenyl)phenyl ester,

isothiocyanic acid, 2-(5-(2-thienyl)-l,2,4-oxadiazol- 3-yl)-5-dimethylaminophenyl ester,

isothiocyanic acid, 3-(5(2-thienyl)1,2,4-oxadiazol-3- yl)-6-acetamidophenyl ester, respectively.

EXAMPLE 28 5 -(2-pyridy1)-3-(p-nitrophenyl)- l ,2,4-oxadiazole cipitate is formed. After the addition of 0.5 ml of BF Et O, the mixture is refluxed for 18 hours. The precipitate which forms upon cooling is filtered off, dried and crystallized from EtOl-l to yield 3.2 g (60%) of product, mp 202203.

EXAMPLE 29 5-( 3-pyridyl )-3-(p-nitrophenyl l ,2,4-oxadiazole hydrochloride Following the above procedure, the reaction of 9.0 g

"(0.05 mole) of p-nitrobenzamidoxime, 9.0 g (0.05 mole) of nicotinic acid chloride hydrochloride, and 3 ml of BF Et O yields 12.3 g (80%) of product, mp 280;

EXAMPLE 3O 5-(4-pyridyl)-3-(p-nitrophenyl)- 1 ,2,4-oxadiazole hydrochloride Following the above procedure, the reaction of 9.0 g (0.05 mole) of p-nitrobenzamidoxime, 7.1 g (0.05

mole) of isonicotinic acid chloride. and 3 ml BF Et O yields 11.6 g of product, mp 238240.

EXAMPLE 31 lsothiocyanic acid, p-[5-(2-pyridyl)-1,2,4-0xadiazol-3-yl] phenyl ester A. A mixture of 2.68 g (0.01 mole) of 5-(2-pyridyl)- 3-(p-nitrophenyD-l,2,4-oxadiazole, 10 ml 10% HQ, 90 ml abs EtOI-I, and 0.27 g of 5% Pd/C is reduced on the Parr hydrogenator at 50 psi until the required amount of H is absorbed. The mixture is filtered and the solid thus isolated is basified (K CO and extracted with CHCl The organic layer is dried (MgSO and evaporated. The solid residue is dissolved in ml glyme and 40 ml H O. 1.0 g (0.01 mole) of CaCO and then 0.8 ml (0.01 mole) of thiophosgene is added dropwise at 0C, The mixture is stirred for 1 hour and then the glyme removed in vacuo at room temperature. The solid is filtered off, dried, and crystallized from CHCl --Et O to yield 1.5 g (54%), mp 143145.

B. A mixture of 0.36 g of sodium borohydride and 0.96 g of sulphur in 50 ml of tetrahydrofuran (THF) is stirred for 0.5 hours at room temperature. A well-stirred suspension'of 2.68 g (0.01 mole) of 5-(2-pyridyl )-3-( p-nitrophenyl l ,2,4-ox adiazole in ml of THF is added'slowly to the above solution of NaBH S /THF and the mixture is refluxed for 24 hours. The solvent is evaporated in vacuo, theresidue stirred with 250 ml of ether and extracted with 10% HCl. The acidic layer is basified (K CO and extracted with CHCl The organic layer is dried (MgSO and evaporated. The solid residue is dissolved in 80 ml glyme and 40 ml H O. 1.0 g (0.01 mole) of CaCO and then 0.8 ml (0.01 mole) of thiophosgene is added dropwise at 0C The mixture is stirred for 1 hour and then the glyme removed in vacuo at room temperature. The,

solid is filtered off, dried, and crystallized from CHCl Et O to yield 1.5 g (54%), mp 143145.

EXAMPLE 32 lsothiocyanic acid, p-[ 5-( 3-pyridyl 1 ,2,4-oxadiazol-3-yl] phenyl ester Following the above procedure, Example 31A the reaction of 3.0 g of 5-( 3-pyridyl)-3-(p-nitrophenyl)- 1,2,4-0xadiazole hydrochloride, 0.3 g of 5% Pd/C, 5 m1 of 10% HCl, 1.0 g of CaCO and 0.8 ml of thiophosgene yields 0.3 (10%) of product, mp 100-104.

EXAMPLE 33 lsothiocyanic acid, p-[ 5-( 4-pyridyl )-1 ,2,4-oxadiazol-3-yl ]phenyl ester Following the above procedure, Example 31A the reaction of 3.0 g of 5-(4-pyridyl)-3-(p-nitropheny1)- l,2,4-oxadiazole hydrochloride, 0.3 g of 5% Pd/C, 5 ml of 10% HCl, 1.0 g of CaCO and 0.8 ml of thiophosgene yields 0.5 g (16%) of product, mp l43-l46.

What is claimed is:

1. A compound of the formula:

wherein R is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, phenyl, Halogen, trifluoromethyl, di(lower alkyl)amino, and lower acetamido; R is pyridyl; and pharmaceutically acceptable salts thereof.

2. The compound of claim 1 wherein R is hydrogen or chlorine.

3. The compound of claim 1 wherein R is hydrogen.

4. A compound of the formula:

wherein R is selected from the group consisting of 2- PATENT NO.

DATED INVENTOR(S) UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION V. L. Narayanan, R. D. Haugwitz Dec It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Col. 1, carbon" Col. 2,

Col. 2, and "Pd/ Col. 6,

Col. 7, oxadiazo Col. 7,

Col. 7,

line 32, the comma between "branched" and "hydro- 38 a comma should be inserted between "N H line 50, "CaCo should read CaCO line "1 ,2,4oxadiazol" should read l,2 ,4- l-.

line 14 "5 (2' should read 5-(2- line 15, "1,2,4oxadiazole" should read Col. 7,

Col. 7, thienyl) line 20, "5 (2" should read 5- (2- line 35, "(5(2-thienyl)" should read 5-(2- UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION 3,853,893 December 10 1974 Patent No. Dated lnventofls) V. L. Narayanan, R. D. Haugwitz Page 2 It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Col. 8 line 51 a comma should be ins t Example 31A er ed following Col 8, line 62 a comma should be inserted f "Example 31A" I Ollowlng Col 9, line 9, "Halogen" should be -halogen-.

9, line 10, the word "lower" 2nd deleted. rence) should be Signed and Scaled this twenty-third Day Of September 1975 [SEAL] Arrest:

RUTH C. MASON C. MARSHALL DANN AIHSII'HX ffiv (unzmixsl'mu'r nj'lalenrx and Trudemurkx 

1. A COMPOUND OF THE FORMULA:
 2. The compound of claim 1 wherein R is hydrogen or chlorine.
 3. The compound of claim 1 wherein R is hydrogen.
 4. A compound of the formula:
 5. The compound of formula 4 having the name isothiocyanic acid, p-(5-(2-pyridyl)-1,2,4-oxadiazol-3-yl)phenyl ester.
 6. The compound of formula 4 having the name isothiocyanic acid, p-(5-(3-pyridyl)-1,2,4-oxadiazol-3-yl)phenyl ester.
 7. The compound of formula 4 having the name isothiocyanic acid, p-(5-(4-pyridyl)-1,2,4-oxadiazol-3-yl)phenyl ester. 